Indoleamine 2,3-dioxygenase in melanoma progression and BRAF inhibitor resistance

Author(s):Show less -

Sandri, Silvana ^[1] ; Watanabe, Luis R. M. ^[1] ; de Oliveira, Erica Aparecida ^[1] ; Faiao-Flores, Fernanda ^[1] ; Migliorini, Silene ^[1] ; Tiago, Manoela ^[1] ; Felipe-Silva, Aloisio ^[2] ; Vazquez, Vinicius de Lima ^[3] ; Souza, Paola da Costa ^[4] ; Lopes Consolaro, Marcia Edilaine ^[5] ; Campa, Ana ^[1] ; Maria-Engler, Silvya Stuchi ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin Chem & Toxicol Anal, Skin Biol Grp, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med FMUSP, Dept Pathol, Sao Paulo - Brazil

^[3] Barretos Canc Hosp, Inst Res & Educ & Melanoma Sarcoma Surg, Barretos, SP - Brazil

^[4] Lab Souza Patol, Maringa, Parana - Brazil

^[5] Univ Estadual Maringa, Dept Clin Anal & Biomed, Maringa, Parana - Brazil

• Document type: Journal article
• Source: PHARMACOLOGICAL RESEARCH; v. 159, SEP 2020.
• Web of Science Citations: 0

Abstract

Indoleamine 2,3-dioxygenase (IDO) is associated with the progression of many types of tumors, including melanoma. However, there is limited information about IDO modulation on tumor cell itself and the effect of BRAF inhibitor (BRAFi) treatment and resistance. Herein, IDO expression was analyzed in different stages of melanoma development and progression linked to BRAFi resistance. IDO expression was increased in primary and metastatic melanomas from patients' biopsies, especially in the immune cells infiltrate. Using a bioinformatics approach, we also identified an increase in the IDO mRNA in the vertical growth and metastatic phases of melanoma. Using in silico analyses, we found that IDO mRNA was increased in BRAFi resistance. In an in vitro model, IDO expression and activity induced by interferon-gamma (IFN gamma) in sensitive melanoma cells was decreased by BRAFi treatment. However, cells that became resistant to BRAFi presented random IDO expression levels. Also, we identified that treatment with the IDO inhibitor, 1-methyltryptophan (1-MT), was able to reduce clonogenicity for parental and BRAFi-resistant cells. In conclusion, our results support the hypothesis that the decreased IDO expression in tumor cells is one of the many additional outcomes contributing to the therapeutic effects of BRAFi. Still, the IDO production changeability by the BRAFi-resistant cells reiterates the complexity of the response arising from resistance, making it not possible, at this stage, to associate IDO expression in tumor cells with resistance. On the other hand, the maintenance of 1-MT off-target effect endorses its use as an adjuvant treatment of melanoma that has become BRAFi-resistant. (AU)

• FAPESP's process: 17/04926-6 - Melanoma and chemoresistance: in vitro and in silico models to exploit therapeutic targets
• Grantee: Silvya Stuchi Maria-Engler
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/26148-5 - The role of TFEB/3 in response to nutrient limitation in MITF-positive and negative melanomas
• Grantee: Érica Aparecida de Oliveira
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 12/05910-2 - Evaluation of RECK and ALX3 expression in cell lines and samples of melanoma patients resistant to vemurafenib (PLX4032) treatment
• Grantee: Manoela Tiago dos Santos
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 11/19045-9 - Methylation of RECK and ALX3 genes in human melanoma
• Grantee: Manoela Tiago dos Santos
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/16554-3 - Emerging genes in melanoma progression and chemoresistance
• Grantee: Érica Aparecida de Oliveira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/05172-4 - Impact of epithelial-mesenchymal transition proteins in vemurafenib chemoresistant melanoma
• Grantee: Fernanda Faião Flores
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/10821-7 - Hsp90 inhibition effects in therapeutic escape pathways in BRAF-mutant melanoma
• Grantee: Fernanda Faião Flores
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor